Alzheimer's disease (AD) is defined neuropathologically by extracellular plaques composed of ?-amyloid (A?) and intracellular tangles consisting of hyperphosphorylated forms of the microtubule-associated protein tau. A? accumulation and hyperphosphorylation of tau are recognized as key events leading to full blown AD neuropathology. Here we propose to use a unique set of small molecule drugs (gamma-secretase modulators and CRFR1 antagonists) to further explore novel AD therapeutics. This application will focus on the efficacy of drugs aimed at both A?- and tau-related pathologies in AD transgenic mice. Our overarching hypothesis is combination therapy aimed to disrupt production of both A?42 and hyperphosphorylated tau will be an efficacious treatment approach for prodromal or early AD.